tbuckley/cabot-search huggingface dataset:
First-in-human study of OBI-999: A globo H-targeting antibody-drug conjugate in patients with advanced solid tumors.
Authors: Apostolia Maria Tsimberidou, Pei Hsu, Tillman E. Pearce
Journal: Journal of Clinical Oncology (2022)

3029 Background: OBI-999 is a novel antibody-drug conjugate, composed of a humanized monoclonal IgG1 antibody which targets the tumor-associated carbohydrate antigen Globo H, conjugated with monomethyl auristatin E (MMAE, vedotin). Upon binding to Globo H, OBI-999 is internalized into the tumor cell, and the linker (Thiobridge) connecting MMAE (an ultrapotent antimitotic agent) to the monoclonal antibody is cleaved by cathepsin B to release MMAE, thereby causing cell cycle arrest by inhibiting tubulin polymerization. We conducted a first-in-human, phase 1, dose-escalation study of OBI-999 monotherapy in patients with advanced cancer (NTC04084366). Methods: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg on Day 1 of a 21-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 15 adult patients were treated. OBI-999 administered on Day 1 of each 21-day cycle was well tolerated up to 1.2 mg/kg, the maximum tolerated dose (MTD). Treatment-related AEs (TRAEs) were noted in 40% (6/15) of patients. TRAEs ≥Grade 3 were noted in 27% (4/15) of patients; of whom 3 had neutropenia and 2 had anemia. OBI-999 exhibited non-linear pharmacokinetics from 0.4 mg/kg to 1.6 mg/kg, with lower clearance at higher doses. A retrospective validated automated immunohistochemistry assessment indicated 50% of patients with advanced solid tumors had high Globo H staining (H-score cutoff ≥100). Of 3 patients treated at the 1.6 mg/kg dose level; 2 developed Grade 4 neutropenia during Cycle 1 and the third developed Grade 4 neutropenia on Cycle 2 Day 15. One patient (1.6 mg/kg) with Grade 4 neutropenia also developed Grade 4 renal insufficiency and died from progressive disease (direct bilirubin, 3.5 mg/dL). Five (33.3%) patients had stable disease (SD), including 1 patient with adenoid cystic carcinoma of the oropharynx (SD for 13 cycles); 1 patient with gastroesophageal junction adenocarcinoma (SD for 8 cycles), and 3 patients with other tumor types (SD for 4, 2, and 2 cycles). Conclusions: We completed the dose-escalation portion of the study. OBI-999 was well tolerated. The recommended phase 2 dose was determined to be 1.2 mg/kg once every 3 weeks. Dose-dependent, non-cumulative neutropenia was dose limiting. We are currently enrolling patients with high Globo H expressing solid tumors (H-score ≥100) in the expansion phase of the study, which includes pancreatic, colorectal, and cancers of other histologic subtypes. Clinical trial information: NTC04084366.
Deconvolution of gene expression for microenvironmental cell types in thymomas.
Authors: Sunil S. Badve, Alper Polar, Jeffrey Peter Solzak, Milan Radovich, Patrick J. Loehrer, Yesim Gokmen-Polar
Journal: Journal of Clinical Oncology (2022)

e20623 Background: Thymomas are rare neoplasms in the anterior mediastinum that account for less than 1% of tumors. The presence of immune cells within the tumor is one of the cardinal features of thymomas. However, the nature of the immune infiltration is not well characterized. Methods: Deconvolution of the gene expression of thymomas in the TCGA-THYM cohort was performed using the CIBERSORT and xCELL programs. Pairwise correlative analyses were performed to study the relationships of cell types and thymoma histological subtypes. Results: The differences in presence of immune cells was better highlighted using xCELL, which identifies 67 categories of cells rather than in the 23 categories identified by CIBERSORT. As expected, there were dramatic differences in the presence of T-cells (almost all subtypes) and B-cells between A/AB and type B (-1, -2, -3) thymomas. A significant difference (P &lt; 0.0001) in different type B thymomas was observed for the presence of monocytes, macrophages, and M1, but not in M2 macrophages. Significant differences in dendritic cells were observed within subtypes of B thymoma. Similarly, statistically significant differences were observed between most subtypes in Immunoscore (except AB/B3) and MicroenvironmentScore (except A/B3; AB/B2 and AB/B3). However, StromalScore differences were observed only in comparisons of type A/AB with B type thymomas (except AB/B3). Interestingly, there also differences in postulated pre-adipocytes, hepatocytes, mesangial cells and osteoblasts in types A vs B, and melanocytes between subtypes of B thymomas. Conclusions: The differences in lymphoid content of the tumor microenvironment is associated with dramatic changes in cell type distribution in subtypes of thymoma. These differences in composition underpin their clinicopathological behavior including incidence of myasthenia and likelihood of recurrence.
Neuroendocrine differentiation in breast carcinoma-clinicopathological characteristics and prognostic significance.
Authors: Saba Shafi, Zaibo Li, Anil Parwani
Journal: Journal of Clinical Oncology (2022)

e12540 Background: Invasive breast carcinoma with neuroendocrine (NE) differentiation has been controversial in terms of its definition and clinical outcome. The recent 5th WHO edition classifies breast carcinoma with NE differentiation into two categories: 1) invasive breast carcinoma, NST (no specific type) with NE features (IBC-NE) (≤90% NE histologic features); 2) NE neoplasm (NEN) (&gt;90% NE features), which is further separated into NE tumor (NET) or NE carcinoma (NEC). However, very little is known about the difference in outcomes, if any, in these three groups of breast carcinomas with NE differentiation. In this study, we examined the clinicopathological characteristics of these three groups of breast cancers and their prognostic significance. Methods: 56 breast cancer patients from 2006 to 2021 were included in this study (IBC-NE: n=41; NET: n=5 and NEC: n=10). Cohort annotation was done by retrospective review of electronic medical records. Results: NEC was significantly associated with higher grade (grade 3 vs. grade1/2) than IDC-NE (90% vs. 26.9%, p=0.0002). IEC-NE showed a significantly greater expression of ER/PR than NET/NEC (ER=100% vs. 64.3%, p&lt;.0001; PR=80.5% vs. 50%, p=0.02). Notably, there was no significant difference in the HER2 status, T stage or survival outcomes between the three groups. NET/NEC had a significantly higher incidence of distant metastases than IDC-NE (46.6% vs. 19.5%, p=0.04). Conclusions: Our data suggest NE neoplasms harbored some different clinicopathologic features from IBC with NE features. In addition, NE neoplasms showed more distant metastasis than IBC with NE features, although no significant difference was observed in overall survival, which may be caused by the small size of current cohort and short follow-up period. [Table: see text]
Online scaffolds: A constructivist approach to oncology fellow learning.
Authors: Sam Brondfield, Matthew Schwede, Tyler Paul Johnson, Shagun Arora
Journal: Journal of Clinical Oncology (2022)

11010 Background: Oncology is a vast and fast-paced field. Fellows must expend significant effort to learn and stay updated. Up-to-date learning tools covering core oncology content in a digestible manner are lacking. Additionally, passive lectures are common in oncology, while constructivist approaches that may improve learning are rare. Therefore, we piloted updatable online modules (“scaffolds”) as a learning tool for oncology fellows. Methods: Author SB, a University of California, San Francisco (UCSF) solid-tumor oncologist, designed 12 scaffolds (breast, non-small cell lung, small cell lung, head/neck, salivary/thyroid, upper gastrointestinal, lower gastrointestinal, germ cell, bladder/renal/adrenal, prostate, melanoma, and sarcoma) using Google Slides between 12/2018 and 6/2019. The scaffolds included bullet points and tables/figures synthesized from the ASCO self-evaluation program textbook’s solid tumor chapters and the National Comprehensive Cancer Network (NCCN) guidelines. We emailed scaffold links to all UCSF and Stanford oncology fellows in 2019-2020, including instructions for fellows to update the scaffolds without exceeding 20 slides per scaffold, 5 lines per slide, or 7 words per line. The scaffolds were reintroduced to new fellows at the beginning of each academic year. SB audited to ensure no erroneous information was added. In December 2021 we reviewed updates tracked in Google Slides and conducted one UCSF and one Stanford focus group with four 1 st -3 rd year fellows each. Results: Between 7/2019 and 12/2021, fellows made 60 updates to the scaffolds, with a mean of 5 updates per scaffold ranging from new trials to changes in management. During the same period, the auditor made 9 updates and found no erroneous fellow updates. Fellow updates occasionally exceeded specified limits, requiring correction. Content analysis revealed that fellows considered the scaffolds to be accessible and succinct learning tools that 1) addressed a dearth of similar resources, 2) served as effective preparation for clinical work and examinations, 3) provided structured information for rapid review, and 4) made subsequent interactions with complex resources such as NCCN guidelines easier. Barriers to fellows updating the scaffolds included lack of ownership and low confidence in judgment regarding appropriate updates. Conclusions: In this two-institution pilot, oncology fellows used and subsequently updated online scaffolds in a constructivist fashion. This model has the potential to fill a crucial gap in available learning resources and can be applied to other specialties. Assigning scaffolds to fellows with faculty mentorship may facilitate ownership and bolster fellow confidence in updating these tools. Individual institutions may update their own versions of the scaffolds to align with institution-specific needs.
Molecular profile and clinical outcomes of renal cell carcinoma brain metastases treated with stereotactic radiosurgery.
Authors: Jennifer Ma, Luke del Balzo, Sari Safaa Khaleel, Jessica Flynn, Zhigang Zhang, Martin H Voss, Benjamin Freeman, A. Ari Hakimi, Chung-Han Lee, Jordan Eichholz, Daniel W. Kelly, Jonathan T. Yang, Boris Mueller, Maria Isabel Carlo, Robert J. Motzer, Brandon S. Imber, Kathryn Beal, Nelson S. Moss, Ritesh Kotecha, Luke Roy George Pike
Journal: Journal of Clinical Oncology (2022)

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p&lt;0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]
Drug response prediction in patient-derived xenografts with data augmentation and multimodal deep learning.
Authors: Alexander Partin, Thomas S. Brettin, Yitan Zhu, Maulik Shukla, Fangfang Xia, Hyunseung Yoo, James M Dolezal, Sara Kochanny, Alexander T. Pearson, Yvonne A. Evrard, James H. Doroshow, Rick L. Stevens
Journal: Journal of Clinical Oncology (2022)

e13572 Background: Prediction of drug response is a critical research area in precision oncology and has been previously explored with large drug screening studies of cancer cell lines (CCLs). Patient-derived xenografts (PDXs) are an appealing platform for preclinical drug studies because the in vivo environment of PDXs helps preserve tumor heterogeneity and usually better mimics drug response of patients with cancer compared to CCLs. Methods: We investigate multimodal neural network (NN) and data augmentation for drug response prediction in PDXs. The multimodal NN learns to predict response using drug descriptors, gene expressions (GE), and histology whole-slide images (WSIs) where the multi-modality refers to tumor features only. The NN uses late integration where separate subnetworks are used to encode the input feature types before concatenation and prediction layers. Median tumor volume per treatment group is assessed relative to the control group to create a binary variable representing response. The data include twelve single-drug and 36 drug-pair treatments resulting in 2,556 single-drug and 2,203 drug-pair response values. Pathology and omics data from 487 PDXs from NCI's Patient Derived Models Repository are used as tumor feature model inputs. We explore whether the integration of WSIs with GE improves predictions as compared with models that use GE alone. We use two methods to address the limited number of response values in the dataset: 1) homogenize drug representations which allows to combine single-drug and drug-pairs into a single dataset, 2) augment drug-pair samples by switching the order of drug features which doubles the sample size of all drug-pair samples. These methods enable us to combine single-drug and drug-pair treatments which results in 6,962 responses, allowing us to train multimodal and unimodal NNs without changing architectures or the dataset. Results: Prediction performance of three unimodal NNs which use GE (um 1 , um 2 , and um 3 ) are compared to assess the contribution of data augmentation methods. NN um 1 that uses the full dataset which includes the original and the augmented drug-pair treatments as well as single-drug treatments significantly outperforms NNs (p-values &lt; 0.01) that ignore either the augmented drug-pairs (um 2 ) or the single-drug treatments (um 3 ). In assessing the contribution of multimodal learning, results show that the multimodal NN (mm) outperforms both unimodal NNs that ignore either the GE (um 4 ) or the WSIs (um 1 ). However, the improvement of mm over um 1 is not statistically significant (p-value &lt; 0.26). Conclusions: Our results show that data augmentation and integration of histology images and GE can help improve prediction performance of drug response in PDXs.[Table: see text]
Associations between interpersonal violence and cancer risk factors for transgender and cisgender people.
Authors: Ash B. Alpert, Sabrina Jamileh Sayegh, Myla S. Strawderman, Scott Cunliffe, Ana Paula Cupertino, Jennifer J. Griggs, Catherine Cerulli
Journal: Journal of Clinical Oncology (2022)

6516 Background: Cancer risk factors for transgender people are largely unexplored. Extreme rates of interpersonal violence experienced by transgender people may increase the risk of cancer. The associations between exposure to interpersonal violence and cancer risk factors have not been investigated. Methods: We searched for experiences of violence in cohorts of 923 transgender and 1846 cisgender people matched by age, follow-up time, and year of the first encounter and measured the association between these experiences and smoking as well as BMI ≥ 40. We then estimated the prevalence ratios for these risk factors using robust Poisson regression models including gender identity, violence, and their interaction, adjusted for age and follow-up time. Results: Transgender people experienced more violence than cisgender people. Among transgender people, there were significantly higher rates of smoking among those who had experienced any type of violence (50% vs 35%, p&lt;.0001) and borderline significantly higher rates of BMI ≥ 40 (23% vs 18%, p=.05). Among cisgender people, significantly higher rates of smoking in those who had experienced violence (52% vs 31%, p&lt;.0001) and significantly higher rates of BMI ≥ 40 (23% vs 11%, p&lt;0.001) were also demonstrated. No statistically significant difference was demonstrated in the association between violence and smoking in transgender compared with cisgender people (prevalence ratio (PR).87, p=.17). A statistically significant difference was demonstrated in the association between violence and BMI ≥ 40 in transgender compared to cisgender people (PR.65, p=.02). Conclusions: Given the association between violence and cancer risk factors, eliminating violence is of profound concern to the oncology community. Violence across the life course is markedly higher in transgender versus cisgender people. Interventions are urgently needed to eliminate violence. Cancer prevention research should investigate the efficacy of methodologies known to impact interpersonal violence, including those modifying structural factors to decrease socioeconomic disparities, stigma, and oppression. [Table: see text]
Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma.
Authors: Xu Yang, Baofeng Lian, Yiran Li, Jinnan Xue, Yunchao Wang, Yanyu Wang, Ziyu Xun, Nan Zhang, Huishan Sun, Junyu Long, Zhijian Song, Leilei Lu, Jie Pan, Lin Zhao, Mei Guan, Xiaobo Yang, Yilei Mao, Xinting Sang, Kai Wang, Hai-Tao Zhao
Journal: Journal of Clinical Oncology (2022)

4101 Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P&lt;0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P&lt;0.001, HR=0.17, P &lt;0.001) and high clinical benefit (CBR) (OR=8.16, P &lt;0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P&lt;0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.